Fundamental cancer metabolism dogma revisited
New research finds that non-dividing colon cancer cells use altered
glucose metabolism to ward off accumulation of toxic reactive oxidative species


Date:
March 22, 2022
Source:
Massachusetts General Hospital
Summary:
Accelerated glucose uptake and metabolism, known as the Warburg
effect, is a feature of a small group of non-dividing cells within
a colon cancer tumor. Intestinal cancer cells rely on Warburg
glycolysis to eliminate toxic reactive oxidative species, not to
provide energy to rapidly dividing cells. Since cancer metabolism
is a heterogeneous feature within cancer cells, new research and
study tools are needed.



FULL STORY ========================================================================== Accelerated glucose uptake and metabolism, known as the Warburg effect,
is a feature of a small group of non-dividing cells within a colon
cancer tumor.

Intestinal cancer cells rely on Warburg glycolysis to eliminate toxic
reactive oxidative species, not to provide energy to rapidly dividing
cells. Since cancer metabolism is a heterogeneous feature within cancer
cells, new research and study tools are needed.


==========================================================================
A new paper in Nature Communicationsreveals new insights into adaptations
made by cancer cells to rewire their metabolism to achieve growth and
survive. Among the discoveries include a challenge to a well-known feature
in cancer metabolism, raising the call for tools to study cancer cell metabolism on a nearly single-cell level.

In the 1920s, Otto Warburg observed that cancer cells metabolically
adapt their glucose pathway in unusual ways. Normally, glucose -- the
main nutrient needed for cells to function -- is sent to the cell's mitochondria to be broken down for energy, a process that requires
oxygen. However, cancer cells appear to rapidly increase their glucose
uptake and directly ferment it into lactate, even in the presence of
oxygen and functional mitochondria. "He called it aerobic glycolysis,
but we know it as the Warburg effect," says author Raul Mostoslavsky,
MD, PhD, scientific co-director of the Mass General Cancer Center and
the Laurel Schwartz Professor of Oncology (Medicine) at Harvard Medical
School. For nearly 15 years researchers have been trying to explain why
cancer cells do this.

In this paper, Mostoslavsky's team studied colon cancer tumors to
learn more.

They developed a fluorescent reporter that stained only a marker
of glycolysis in cells of the tumor. Using this reporter and a mass spectrometry imaging approach developed by collaborator Nathalie Agar of Brigham and Women's Hospital, the researchers found that not all cells
within the colon cancer cell relied on Warburg glycolysis. "We found
that this metabolic adaptation does not happen in the whole tumor, only
in a heterogeneous group that were not dividing," says Mostoslavsky. His
team had published this heterogeneous feature in squamous cell carcinoma
but this is the first time it has been shown in colon cancer, and in non-dividing cells.

"What really surprised us is that when we stained the tumor cells with
a marker of cell proliferation, they were mutually exclusive," adds Mostoslavsky. Within fully transformed colon cancers, the cells that were
doing Warburg glycosis were not dividing. "This completely challenges
the dogma of the Warburg effect," he adds. For the past 10 to 15 years,
most researchers working in cancer metabolism have held that cancer
cells do Warburg glycolysis to send glucose for biomass production, or
rapid proliferation. "Instead, we found that the main reason they were
doing it was to reduce reactive oxygen species, or ROS." Reactive oxygen species damage cells during glucose breakdown and energy production:
"The cells do Warburg metabolism to protect against accumulation of ROS."
This research showed that indeed Warburg glycolysis is real and functional
in cancer cells as a needed adaptation. "But it's not for the reason we
used to think," says Mostoslavsky. "This means we need to rethink how we
are studying cancer metabolism." Much of the advancements made in the
past 10 years studying cancer metabolism come from mass spectrometry
analysis of metabolomics, which require many cells. The problem is
a lack of means for analyzing cellular heterogeneity. "If metabolic
adaptation happens in some cancer cells or not in others, you will not
be able to determine that with the current technologies that exist,"
he says. "We now know Warburg glycolysis is a heterogeneous feature
happening in tumors so we need to develop tools that will allow us to investigate tumors in a single-cell fashion." In this paper, the team
relied on a novel mass spectrometry imaging tool developed to achieve
data almost at a single cell resolution. Says Mostoslavsky: "It is
clear that cancer metabolism is highly heterogeneous so we will need new
tools like this to study and define these metabolic features in tumors."
Other authors of the study include Carlos Sebastian, Christina Ferrer,
Maria Serra, Jee-Eun Choi, Nadia Ducano, Alessia Mira, Manasvi Shah,
Sylwia Stopka, Andrew Perciaccante, Claudio Isella, Daniel Moya-Rull,
Marianela Vara-Messler, Silvia Giordano, Elena Maldi, Niyata Desai,
Diane Capen, Enzo Medico, Murat Cetinbas, Ruslan Sadreyev, Dennis Brown,
Miguel Rivera, Anna Sapino, and David Breault.

This work was supported by grants from the National Institutes of
Health, FPRC 5 per mille 2011 MIUR, FPRC 5 per mille 2014 MIUR, RC 2018 Ministero della Salute, and the European Union's Horizon 2020 Research
and Innovation Program.


========================================================================== Story Source: Materials provided by Massachusetts_General_Hospital. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Carlos Sebastian, Christina Ferrer, Maria Serra, Jee-Eun Choi, Nadia
Ducano, Alessia Mira, Manasvi S. Shah, Sylwia A. Stopka, Andrew J.

Perciaccante, Claudio Isella, Daniel Moya-Rull, Marianela
Vara-Messler, Silvia Giordano, Elena Maldi, Niyati Desai, Diane
E. Capen, Enzo Medico, Murat Cetinbas, Ruslan I. Sadreyev, Dennis
Brown, Miguel N. Rivera, Anna Sapino, David T. Breault, Nathalie
Y. R. Agar, Raul Mostoslavsky. A non- dividing cell population with
high pyruvate dehydrogenase kinase activity regulates metabolic
heterogeneity and tumorigenesis in the intestine.

Nature Communications, 2022; 13 (1) DOI: 10.1038/s41467-022-29085-y ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220322122803.htm

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